Lithium efflux from erythrocytes of normal and manic-depressive subjects has been measured in vitro. The efflux rate constant is substantially repressed during chronic administration of lithium carbonate to most patients. The repression has been found to be reversible within days to weeks after cessation of lithium carbonate ingestion. The mechanism of repression of lithium efflux will be investigated at the molecular level. Recent experiments with inhibitors of the erythrocyte calcium pump have shown that these inhibitors also produce a substantial repression of lithium efflux. Activation of lithium efflux has been shown to occur with activators of 2,3 diphosphoglycerate phosphatase. These recent observation on inhibitors and activators of lithium efflux will be utilized as probes to obtain a detailed view of the mechanism of lithium tranport, and will be further applied to the investigation of the normal physiologcal controls which are altered when the lithium efflux rate constant is repressed as a consequence of lithium carbonate ingestion.